Combination composition

ABSTRACT

An intravenous composition for providing relief for pain and/or inflammation, the composition having ibuprofen and paracetamol in combination for delivering to a human at each dose:a) approximately 125 mg to approximately 175 mg ibuprofen in combination with approximately 475 mg to approximately 525 mg paracetamol; orb) approximately 275 mg to approximately 325 mg ibuprofen in combination with approximately 975 mg to approximately 1,025 mg paracetamol.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 16/149,109, filed Oct. 1, 2018, which is a continuation applicationof U.S. application Ser. No. 14/832,154, filed Aug. 21, 2015, which is acontinuation application of U.S. application Ser. No. 13/882,953, filedMay 1, 2013, which is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/NZ2011/000226, filed Oct. 26, 2011,which claims the benefit of New Zealand Patent Application No. 589011,filed Nov. 4, 2010, the entire contents of the aforementionedapplications are hereby incorporated herein by reference.

FIELD OF INVENTION

This invention relates to a combination composition comprisingparacetamol and ibuprofen. A particularly preferred embodiment of theinvention relates to a combination composition containing these activeingredients for use in relieving pain and/or inflammation.

BACKGROUND

Combinations of paracetamol and ibuprofen are known, for example asrelatively low dose tablets having 150 mg ibuprofen and 500 mgparacetamol. However there is a need for a medication, particularly onewhich can be administered intravenously in a hospital environment. It isan object of an embodiment of the present invention to go at least someway towards facilitating this.

Definitions

References in this specification to an adult mean a person weighing 50kg or more.

References in this specification to a child mean a person weighing lessthan 50 kg.

While ibuprofen and paracetamol are specifically referred to in thisspecification, suitable other pharmaceutically acceptable forms of thesetwo actives (eg salts, etc) may also be used and are intended to beembraced in the claims by references to the actives per se, with theweight amounts adjusted accordingly. For example, when a salt form isused, sufficient quantity may be included to meet the desired amount ofthe compound per se (eg, 513 mg ibuprofen lysinate, or 553 mg ibuprofenarginine salt, corresponds with 300 mg ibuprofen). Thus, for example, areference to 300 mg ibuprofen may be construed as sufficient to embracethe therapeutically equivalent amount of ibuprofen lysinate or ibuprofenarginine.

The term “comprising” and derivatives thereof, eg “comprises”, if andwhen used in relation to a combination of features should not be takento exclude the possibility of the combination having further unspecifiedfeatures.

SUMMARY OF INVENTION

According to one aspect of the invention there is provided anintravenous composition for providing relief for pain and/orinflammation, the composition having ibuprofen and paracetamol incombination for delivering to a human at each dose:

-   -   a) approximately 125 mg to approximately 175 mg ibuprofen in        combination with approximately 475 mg to approximately 525 mg        paracetamol; or    -   b) approximately 275 mg to approximately 325 mg ibuprofen in        combination with approximately 975 mg to approximately 1,025 mg        paracetamol.

Preferably the composition is for dosing on approximately a 6 hourlybasis.

Preferably the composition comprises:

-   -   a) approximately 150 mg ibuprofen in combination with        approximately 500 mg paracetamol; or    -   b) approximately 300 mg ibuprofen in combination with        approximately 1,000 mg paracetamol.

Preferably the composition is in the form of a solution.

A further aspect of the invention comprises the use of paracetamol andibuprofen in the manufacture of an intravenous medicament for treatingpain and/or inflammation in a human wherein the medicament comprises, ona per dose basis:

-   -   a) approximately 125 mg to approximately 175 mg ibuprofen in        combination with approximately 475 mg to approximately 525 mg        paracetamol; or    -   b) approximately 275 mg to approximately 325 mg ibuprofen in        combination with approximately 975 mg to approximately 1,025 mg        paracetamol.

Preferably the composition is for dosing on approximately a 6 hourlybasis

Preferably the composition comprises:

-   -   a) approximately 150 mg ibuprofen in combination with        approximately 500 mg paracetamol; or    -   b) approximately 300 mg ibuprofen in combination with        approximately 1,000 mg paracetamol.

Preferably the composition is in the form of a solution.

A further aspect of the invention comprises a method of treating painand/or inflammation by administering to a human, intravenously, amedicament comprising:

-   -   a) approximately 125 mg to approximately 175 mg ibuprofen in        combination with approximately 475 mg to approximately 525 mg        paracetamol; or    -   b) approximately 275 mg to approximately 325 mg ibuprofen in        combination with approximately 975 mg to approximately 1,025 mg        paracetamol.

Preferably the composition is administered on a 6 hourly basis.

Preferably the composition comprises:

-   -   a) approximately 150 mg ibuprofen in combination with        approximately 500 mg paracetamol; or    -   b) approximately 300 mg ibuprofen in combination with        approximately 1,000 mg paracetamol.

Preferably the composition is in the form of a solution.

DETAILED DESCRIPTION

In a preferred embodiment of the invention an intravenous solution isprovided for use in treating pain or inflammation in human patients. Thesolution is a combination medication comprising ibuprofen, paracetamoland suitable excipients as will be known to those with ordinary skillsin the art of formulating intravenous medicines. The excipients mayinclude suitable antioxidants, pH modulators, buffering agentsisotonicity agents and purified water.

The following examples illustrate preferred embodiments of the inventionin the form of intravenous infusion solutions.

Example 1 Example 2 mg/100 ml mg/100 ml Ingredient vial vial Ibuprofen150 300 Paracetamol 500 1,000

For each of the above examples the two active ingredients are mixed withsuitable standard excipients to give the vial volumes indicated above.

The infusion solutions are for delivery to a patient as a full dose, forexample in each case the patient receives the complete vial contents asa 15 minute infusion every 6 hours. Example 1 is a child's dose andExample 2 is an adult dose. In the case of very young or small childrenonly part of the vial contents of Example 1 may be dosed on a bodyweight basis, commensurate with instructions from the prescribingphysician.

Paracetamol at 4,000 mg per 24 hour period, taken in 4 doses of 1,000 mgevery 6 hours, has long been considered sufficient for relieving lowlevel pain but for many patients suffering significant pain, for examplein some post operative situations, it is not sufficient. However it isgenerally not advisable to dose paracetamol at more than 1,000 mg perdose or at more than 4,000 mg per 24 hour period, because to do so canlead to undesirable side effects.

It is known to treat severe pain with ibuprofen in doses of 800 mg every8 hours. However, doses as high as 800 mg can lead to undesirable sideeffects, for example adverse cardio renal conditions, renal problems,thrombotic risks and gastrointestinal bleeding. Reducing the amount ofibuprofen at each dosing event may reduce the risk of side effects butat the same time may provide substantially less pain relief.

Surprisingly, an intravenous medicine comprising 150 mg or 300 mgibuprofen, plus 500 mg or 1,000 mg paracetamol, respectively, for useevery 6 hours, provides adequate pain relief for some patients thatwould otherwise need to take, respectively, 400 mg or 800 mg every 8hours. The lower dose of ibuprofen reduces the risk of undesirable sideeffects in some patients but the effectiveness of the medication forsuch patients is not compromised due to the presence of the paracetamol.This is unexpected because for many patients one would not predict thepresence of paracetamol to assist to any significant degree. Thecombination is counterintuitive because, for example, 400 mg ibuprofenfor relief of pain is generally seen as an 8 hourly medicament, and1,000 mg paracetamol is generally seen as a 6 hourly medicament. Thenormal dosage regimens for these active ingredients are out of step withone another, ie 8 hourly versus 6 hourly, and thus to the normallyskilled artesian they would not, at the doses of the present invention,be seen as suitable for a combination medication.

Similar considerations apply in the case of 150 mg ibuprofen, incombination with 500 mg paracetamol, for treating children sufferingfrom pain. In this regard, surprisingly, some children that wouldnormally be given 200 mg ibuprofen for pain can be given, as analternative, 150 mg ibuprofen in combination with 500 mg paracetamol.

Administering an intravenous combination solution comprising 300 mgibuprofen plus 1,000 mg paracetamol to an adult, or an intravenouscombination solution comprising 150 mg ibuprofen plus 500 mg paracetamolto a child, on an ongoing basis, for example every 6 hours, provides asurprising level of pain relief compared to administering the same dosesorally, for example by way of a tablet. The intravenous administrationreduces the need for rescue pain relief in at least some patientsrecovering from surgical procedures. The intravenous administration mayfor example be by way of injection or infusion.

Example 3

In a particular embodiment of the invention an intravenous solution maybe prepared by mixing the following active ingredients and excipients:

ACTIVE INGREDIENTS AMOUNT Paracetamol 1000 mg Ibuprofen arginine  553 mgEXCIPIENTS AMOUNT Reduced glutathione (as antioxidant)  20 mg Sodiumhydroxide or hydrochloric sufficient to give acid (as a pH modulator) apH of 5-6 Sodium citrate  10 mg Sodium chloride sufficient to impart (asan isotonicity agent) isotonicity Purified water Sufficient to bring thecomposition to 100 ml

The solution is for administration to an adult as a single intravenousdose and further equivalent doses may be repeated every 6 hours if needbe, commensurate with instructions from the prescribing physician.

Example 4

In a further embodiment of the invention an intravenous solution may beprepared by mixing the following active ingredients and excipients:

ACTIVE INGREDIENTS AMOUNT Paracetamol   500 mg Ibuprofen arginine 276.5mg EXCIPIENTS AMOUNT Reduced glutathione   10 mg (as antioxidant) Sodiumhydroxide or hydrochloric sufficient to acid (as a pH modulator) give apH of 5-6 Sodium citrate    5 mg (as a buffering agent) Sodium chloridesufficient to (as an isotonicityagent) impart isotonicity Purified waterSufficient to bring the composition to 100 ml

The solution is for administration to a child as a single intravenousdose and further equivalent doses may be repeated every 6 hours if needbe, commensurate with instructions from the prescribing physician.

While some preferred forms of the invention have been described by wayof example it should be appreciated that modifications and improvementscan occur without departing from the scope of the following claims.

1. A method of treating pain by intravenously administering to a human,100 ml of an aqueous solution comprising: a) 150 mg ibuprofen incombination with 500 mg paracetamol; or b) 300 mg ibuprofen incombination with 1000 mg paracetamol.
 2. The method according to claim1, wherein the aqueous solution is administered on a 6 hourly basis. 3.The method of claim 1, wherein the aqueous solution comprises 150 mgibuprofen in combination with 500 mg paracetamol.
 4. The method of claim1, wherein the aqueous solution comprises 300 mg ibuprofen incombination with 1000 mg paracetamol.
 5. The method of claim 2, whereinthe aqueous solution comprises 150 mg ibuprofen in combination with 500mg paracetamol.
 6. The method of claim 2, wherein the aqueous solutioncomprises 300 mg ibuprofen in combination with 1000 mg paracetamol.
 7. Amethod of treating pain by intravenously administering to a human, anaqueous solution comprising: a) 150 mg ibuprofen in combination with 500mg paracetamol; or b) 300 mg ibuprofen in combination with 1000 mgparacetamol, wherein the administration takes place over 15 minutes. 8.The method according to claim 7, wherein the aqueous solution isadministered on a 6 hourly basis.
 9. The method of claim 7, wherein theaqueous solution comprises 150 mg ibuprofen in combination with 500 mgparacetamol.
 10. The method of claim 7, wherein the aqueous solutioncomprises 300 mg ibuprofen in combination with 1000 mg paracetamol. 11.The method of claim 8, wherein the aqueous solution comprises 150 mgibuprofen in combination with 500 mg paracetamol.
 12. The method ofclaim 8, wherein the aqueous solution comprises 300 mg ibuprofen incombination with 1000 mg paracetamol.
 13. A method of treating pain byintravenously administering to a human, 100 ml of an aqueous solutioncomprising: a) 150 mg ibuprofen in combination with 500 mg paracetamol;or b) 300 mg ibuprofen in combination with 1000 mg paracetamol, whereinthe administration takes place over 15 minutes.
 14. The method accordingto claim 13, wherein the aqueous solution is administered on a 6 hourlybasis.
 15. The method of claim 13, wherein the aqueous solutioncomprises 150 mg ibuprofen in combination with 500 mg paracetamol. 16.The method of claim 13, wherein the aqueous solution comprises 300 mgibuprofen in combination with 1000 mg paracetamol.
 17. The method ofclaim 14, wherein the aqueous solution comprises 150 mg ibuprofen incombination with 500 mg paracetamol.
 18. The method of claim 14, whereinthe aqueous solution comprises 300 mg ibuprofen in combination with 1000mg paracetamol.